Mechanism of MR and type of dysfunction
Cause of mitral regurgitation (e.g., of lesion)
Ischemic
Nonischemic
Organic/primary
Type I
• Infectious/endocarditis (perforation)
• Degenerative (annular calcification)
• Congenital (cleft leaflet)
Type II
Ruptured papillary muscle
• Infectious/endocarditis (ruptured chord)
• Traumatic (ruptured chord)
• Rheumatic (elongated chords)
• Degenerative (billowing/flail leaflets)
Type IIIa
• Rheumatic (e.g., fibrotic chords)
• Iatrogenic (radiation/drug)
• Inflammatory (lupus, anticardiolipin, eosinophilic, fibrosis, endocardial diseases)
Functional/secondary
Type I and Type IIIb
Functional ischemic MR
• Cardiomyopathy, myocarditis
• LV dysfunction (any cause)
Grading the degree of MR has its limitations, so a comprehensive process to obtain multiple measurements by transthoracic echocardiography (TTE), TEE, and Doppler color flow imaging is essential. A more comprehensive assessment should be made—with cardiac magnetic resonance imaging, if necessary—to further quantify the degree of MR and resolve any discrepancies in the echocardiographic findings.
In most cases, TTE can identify the mitral valve pathology. When additional information is required, TEE provides a more precise and detailed assessment of the MV. It has better spatial resolution, allowing more accurate MR quantification, especially with regard to jet color characteristics. In addition, 3-D visualization of the valve provides further confirmatory evidence of the mitral leaflet abnormality and delineates its exact location [46].
Identifying the cause of the MR is essential for the patient’s preoperative and postoperative management, as well as for planning the operative strategy. Obtaining an echocardiogram while the patient is not under anesthesia is important because the loading conditions of the heart are not altered; the degree of regurgitation can be significantly reduced and therefore underestimated when the patient is under anesthesia. Assessing not only leaflet pathology but also the direction of the single or multiple regurgitant jets is also important in planning the operative strategy.
The quantitative assessment of the MV by echocardiography classifies the degree of regurgitation into four grades (I–IV). The degree of severity can be graded further by calculating the effective regurgitant orifice area (EROA), regurgitant volume, and regurgitant fraction. It is important to understand that the quantitative parameters used to assess of the severity of MR are different with degenerative and functional MV disease.
With MR, anatomic malcoaptation of the mitral leaflets occurs during systole, and this results in an effective regurgitant orifice (ERO) that allows abnormal flow from the LV into the left atrium (LA) during systole. The ERO is influenced by the pressure gradient between the LV and the LA and may be dynamic, depending on the cause of the MR [47]. Increased afterload or ventricular volume can increase ERO, whereas decreased afterload and improved contractility can reduce ERO [48]. The sum of the regurgitant flow through the ERO during systole is the regurgitant volume (RVol) accumulated in the LA. This RVol reenters the LV during the subsequent diastole, resulting in volume overload of the LA and LV and ensuing manifestations and consequences of disease. In acute MR, the LA is small and has low compliance; as a result, any amount of RVol increases LA pressure. For this reason, acute MR is often not well tolerated and results in significant symptoms and hemodynamic changes.
The hemodynamic responses of the heart to chronic, slowly progressive MR are different from those associated with acute MR. These responses to the excessive chronic volume overload caused by MR initially result in a chronic compensated stage of volume overload, which, if uncorrected, can progress to a decompensated stage with irreversible LV dysfunction. In chronic MR, the LA remodels to accommodate the RVol so that the LA pressure is maintained; for this reason, even severe MR may be tolerated hemodynamically and symptomatically for a long period, even years [49]. Thus, in the chronic compensated state, the LV is initially unloaded by the low-resistance runoff into the LA, which is then countered by an increase in LV size to maintain wall stress at normal levels [50, 51]. In the chronic compensated stage, LV enlargement is the chief compensatory mechanism, allowing a greater LV volume as a result of the MR while maintaining normal diastolic pressures. The chronic overload from this RVol eventually leads to LV hypertrophy and dilatation [52]. The LV end-diastolic volume, end-systolic volume, and wall stress all increase, causing the LV to become more spherical [53, 54].
In the chronic compensated state, adequate forward cardiac output and normal filling pressures are maintained. Sequelae of this pathophysiology, such as atrial fibrillation due to continued left atrial enlargement, and pulmonary hypertension due to continued pressure overload, are the presenting clinical phenomena for some patients. Diastolic dysfunction may also be present but is often difficult to diagnose and quantify; it may account for symptomaticity and reduced functional capacity in patients with normal systolic function [55, 56]. Many patients remain asymptomatic in this state, and normalized preload and wall stress sometimes help the LV maintain normal contractility. Patients can remain in a chronic compensated stage for years to decades after the onset of MR.
However, eventually, the consequence of these changes is progressive LV enlargement beyond the compensated stage; the ensuing ventricular dysfunction can be severe [56]. Progressive LV enlargement may be due to increased severity of MR, continued compensatory chamber enlargement, or both. The LV enlargement can exacerbate MR because of ventricular-valvular interdependence, resulting in a vicious cycle of worsening MR and LV dysfunction. Preload and afterload changes can make the degree of this LV dysfunction difficult to characterize [57]. Nevertheless, these cumulative effects can result in irreversible LV dysfunction, leading to decompensated MR, with an ensuing poor prognosis.
In primary MR, mild MR is defined as a mitral RVol <30 mL, a regurgitant fraction (RF) <30%, and an EROA <0.2 cm2, whereas severe MR is defined as a RVol ≥60 mL with an RF ≥50% and an EROA ≥0.4 cm2. Other indicators of severe MR include a vena contracta width ≥0.7 cm with a large central regurgitant jet occupying >40% of the LA area or with a wall-impinging jet of any size, as well as blunting of the systolic component with systolic flow reversal in the pulmonary veins. Additional supportive signs include a very dense, early-peaking triangular jet on a continuous-wave Doppler echocardiogram and a peak mitral inflow velocity >120 cm/s [58].
Stages of primary MR
Grade | Definition | Valve anatomy | Valve hemodynamicsa | Hemodynamic consequences | Symptoms |
|---|---|---|---|---|---|
A | At risk of MR | • Mild mitral valve prolapse with normal coaptation • Mild valve thickening and leaflet restriction | • No MR jet or small central jet area <20% LA on Doppler • Small vena contracta <0.3 cm | • None | • None |
B | Progressive MR | • Severe mitral valve prolapse with normal coaptation • Rheumatic valve changes with leaflet restriction and loss of central coaptation • Prior IE | • Central jet MR 20–40% • LA or late systolic eccentric jet MR • Vena contracta <0.7 cm • Regurgitant volume <60 mL • Regurgitant fraction <50% • ERO <0.40 cm2 • Angiographic grade 1–2+ | • Mild LA enlargement • No LV enlargement • Normal pulmonary pressure | • None |
C | Asymptomatic severe MR | • Severe mitral valve prolapse with loss of coaptation or flail leaflet • Rheumatic valve changes with leaflet restriction and loss of central coaptation • Prior IE • Thickening of leaflets with radiation heart disease | • Central jet MR >40% LA or holosystolic eccentric jet MR • Vena contracta ≥0.7 cm • Regurgitant volume ≥ 60 mL • Regurgitant fraction ≥50% • ERO ≥0.40 cm2 • Angiographic grade 3–4+ | • Moderate or severe LA enlargement • LV enlargement • Pulmonary hypertension may be present at rest or with exercise • C1: LVEF >60% and LVESD <40 mm • C2: LVEF ≤60% and LVESD ≥40 mm | • None |
D | Symptomatic severe MR | • Severe mitral valve prolapse with loss of coaptation or flail leaflet • Rheumatic valve changes with leaflet restriction and loss of central coaptation • Prior IE • Thickening of leaflets with radiation heart disease | • Central jet MR >40% LA or holosystolic eccentric jet MR • Vena contracta ≥0.7 cm • Regurgitant volume ≥ 60 mL • Regurgitant fraction ≥50% • ERO ≥0.40 cm2 • Angiographic grade 3–4+ | • Moderate or severe LA enlargement • LV enlargement • Pulmonary hypertension present | • Decreased exercise tolerance • Exertional dyspnea |
Progressive, or grade B, MR is characterized by severe mitral prolapse with normal coaptation, rheumatic changes with leaflet restriction, and loss of coaptation, or by prior infective endocarditis. The central jet measures 20–40% of the LA or may be a late systolic eccentric jet. The vena contracta measures <0.7 cm and has a regurgitant volume of <60 mL, an RF <50%, and an EROA <0.4 cm2. Concomitant MV repair is now a class IIa recommendation for patients with grade B MR undergoing cardiac surgery for other indications [26].
Asymptomatic severe MR, or grade C, can be characterized similarly to grade B, in that echocardiographic findings are consistent with rheumatic changes or prior infective endocarditis. Grade C severity is often distinguished from Grade B by prolapse with the loss of leaflet coaptation or a flail leaflet, or by thickening of the leaflets associated with radiation heart disease. Defining echocardiographic measurements are a central jet >40% of the LA, a holosystolic eccentric jet, vena contracta >0.7 cm, regurgitant volume >60 mL, RF >50%, and an EROA >0.4 cm2. Class Ia indications for surgery for asymptomatic severe MR include LV dysfunction (defined by an LVEF of 30–60% or a LV end-systolic diameter >40 mm) and cardiac surgery for other indications, during which the MV can be repaired concomitantly. Current guidelines make a class IIa recommendation for repair for asymptomatic severe MR in patients with preserved LV function, for whom the likelihood of a successful and durable repair is >95%, with an expected mortality <1% when performed at a Heart Valve Center of Excellence [26].
Symptomatic severe MR , or grade D, is identified by the same anatomic findings and echocardiographic measurements used to identify asymptomatic MR. Symptoms of severe MR include decreased exercise tolerance and exertional dyspnea. Mitral valve surgery is a class I recommendation for patients with an LVEF >30% and symptomatic severe MR. In addition, considering MV surgery in patients with an LVEF <30% now carries a class IIb recommendation [26].
In secondary MR, the thresholds of 0.4 cm2 or 60 mL/beat may still be considered severe on the basis of several arguments. A lower RVol might still represent significant overload for a compromised LV. Because the total cardiac output of the ventricle is generally lower than in primary MR with preserved LV function, the 60-mL threshold may not be reached despite a >50% RF. In addition, with secondary MR, the orifice is usually crescentic along the commissural line and may underestimate the orifice area when one uses the 2D PISA method (in contrast to 3D), which inherently assumes a hemispheric flow convergence [59].
The most recent (2017) guideline the ERO delineating “severe” MR was changed from 0.2 cm2 to 0.4 cm2 recognizing that LV volume interacted with orifice area in delineating severity. In the typically dilated LV in patients with MR, an ERO of 0.4 cm2 is usually associated with a regurgitant fraction of 50% while in smaller LVs the ERO may be less than 0.4 and still be consistant with severe MR. Most importantly, no single parameter should ever be used to assess MR severity in either primary or secondary MR. Rather all parameters including physical examination should be integrated to arrive at an estimation.
Cardiac magnetic resonance (CMR) can be used not only to assess the cause but also, more importantly, to quantify the severity of MR. Use of CMR is indicated when echocardiographic and clinical findings do not agree. It is extremely useful for quantifying multiple or eccentric MR jets that are difficult to evaluate by echocardiography. In addition, CMR can assess cardiac size and function and LV scar burden, along with their interaction, in patients with secondary MR [60]. Most comparisons of CMR and TTE show concordance in evaluating the degree of primary MR, although not secondary MR [61, 62].
The 2017 AHA/ACC guidelines classify secondary MR into the same 4 classes as primary MR: grade A, at risk of MR; grade B, progressive MR; grade C, asymptomatic severe MR; and grade D, symptomatic severe MR. Patients at risk of secondary MR have normal valve leaflets, chords, and annular structure, with associated coronary disease or cardiomyopathy. Echocardiography reveals no MR jet or a jet <20% of the LA, and a vena contracta <0.3 cm. No intervention is recommended for patients at risk of secondary MR [26].
Stages of secondary MR
Grade | Definition | Valve anatomy | Valve hemodynamicsa | Associated cardiac findings | Symptoms |
|---|---|---|---|---|---|
A | At risk of MR | • Normal valve leaflets, chords, and annulus in a patient with coronary disease or cardiomyopathy | • No MR jet or small central jet area <20% LA on Doppler • Small vena contracta <0.30 cm | • Normal or mildly dilated LV size with fixed (infarction) or inducible (ischemia) regional wall motion abnormalities • Primary myocardial disease with LV dilation and systolic dysfunction | • Symptoms due to coronary ischemia or HF may be present that respond to revascularization and appropriate medical therapy |
B | Progressive MR | • Regional wall motion abnormalities with mild tethering of mitral leaflet • Annular dilation with mild loss of central coaptation of the mitral leaflets | • ERO <0.40 cm2,b • Regurgitant volume <60 mL • Regurgitant fraction <50% | • Regional wall motion abnormalities with reduced LV systolic function • LV dilation and systolic dysfunction due to primary myocardial disease | • Symptoms due to coronary ischemia or HF may be present that respond to revascularization and appropriate medical therapy |
C | Asymptomatic severe MR | • Regional wall motion abnormalities and/or LV dilation with severe tethering of mitral leaflet • Annular dilation with severe loss of central coaptation of the mitral leaflets | • ERO ≥0.40 cm2,b • Regurgitant volume ≥60 mL • Regurgitant fraction ≥50% | • Regional wall motion abnormalities with reduced LV systolic function • LV dilation and systolic dysfunction due to primary myocardial disease | • Symptoms due to coronary ischemia or HF may be present that respond to revascularization and appropriate medical therapy |
D | Symptomatic severe MR | • Regional wall motion abnormalities and/or LV dilation with severe tethering of mitral leaflet • Annular dilation with severe loss of central coaptation of the mitral leaflets | • ERO ≥0.40 cm2,b • Regurgitant volume ≥60 mL • Regurgitant fraction ≥50% | • Regional wall motion abnormalities with reduced LV systolic function • LV dilation and systolic dysfunction due to primary myocardial disease | • HF symptoms due to MR persist even after revascularization and optimization of medical therapy • Decreased exercise tolerance • Exertional dyspnea |
Secondary progressive MR is identified by wall motion abnormalities on echocardiography, with mild tethering of the mitral leaflet or with annular dilation and loss of central coaptation of the leaflets. The EROA is <0.4 cm2, regurgitant volume is <60 mL, and the RF is <50%. Mitral valve repair (not replacement) may be considered for secondary progressive MR in patients undergoing cardiac surgery for other indications (class IIb recommendation) [26].
Asymptomatic and symptomatic severe secondary MR are associated with regional wall motion abnormalities, LV dilatation with severe tethering of a mitral leaflet, or annular dilation with severe loss of mitral leaflet coaptation. The EROA is >0.4 cm2, with a regurgitant volume >60 mL or an RF >50%. Asymptomatic patients may have symptoms due to coronary ischemia or heart failure, but these symptoms respond to revascularization and medical therapy. In contrast, patients considered symptomatic have heart failure symptoms that persist after revascularization and do not respond to optimized medical therapy. These symptoms may include decreased exercise tolerance and exertional dyspnea. Mitral valve surgery is recommended for both asymptomatic and symptomatic severe secondary MR in patients undergoing coronary artery bypass grafting or AVR (class IIa). Mitral valve repair or replacement may be considered for symptomatic patients undergoing other cardiac operations (class IIb) [26].
Nonischemic functional MR is most often due to severe chronic LV volume overload with unknown or idiopathic causes. Other advanced valvular heart disease is the second most common cause. Functional MR can be found in 40% of patients with heart failure due to dilated cardiomyopathy [63]. Functional, ischemic MR is increasingly prevalent as the population ages and as more patients survive myocardial infarction and live with severe ischemic heart disease. Ischemic MR can result in changes in mitral annular geometry and regional and global LV geometry and function, abnormal leaflet motion, increased distance between papillary muscles, misalignment of papillary muscles, and apical tethering of the leaflets with restricted systolic leaflet motion and a typical Carpentier type IIIb pattern of dysfunction [64, 65]. Thus, ventricular dysfunction, whether the cause is ischemic or nonischemic, can cause or contribute substantially to the development of MR. Technologies aimed at ameliorating ventricular dysfunction may therefore be important in treating MR in such patients.
Mitral Valve Stenosis
Mitral valve stenosis is classified into stages similar to the grades used to classify MR: stage A, at risk of MS; stage B, progressive MS; stage C, asymptomatic severe MS; and stage D, symptomatic severe MS. Patients at risk of MS may have MV doming identified by echocardiography, but with normal transmitral velocities. No intervention is recommended at this stage [26].
Patients with progressive MS may have rheumatic changes with associated commissural fusion and diastolic doming. The planimetered valve area is <1.5 cm2, transmitral flow velocities are increased, and the diastolic pressure half-time is <150 ms. In contrast, both asymptomatic and symptomatic severe MS are associated with similar anatomy on echocardiography but with a planimetered valve area <1.5 cm2, a diastolic pressure half-time >150 ms, and elevated (>30 mmHg) pulmonary artery systolic pressures. Very severe MS is further characterized by MV areas <1 cm2 and diastolic pressure half-times >220 ms. Symptoms associated with MS can include decreased exercise tolerance and exertional dyspnea [26].
For patients with mitral stenosis, percutaneous balloon commissurotomy is often the first-line therapy when anatomically feasible. Candidates for balloon commissurotomy must be free of moderate or severe MR and must have no left atrial thrombus. The AHA/ACC guidelines currently make a class I recommendation for percutaneous balloon commissurotomy in symptomatic patients with severe MS and favorable valve morphology. Furthermore, patients with asymptomatic severe or very severe MS may be considered for balloon commissurotomy. However, for patients with severe symptomatic MS who are not candidates for balloon commissurotomy or for whom it has failed, MV surgery is recommended. Additionally, concomitant MV surgery is recommended for patients with moderate or severe MS undergoing cardiac surgery for other indications. Lastly, MV surgery with ligation of the left atrial appendage can be considered for patients with severe MS who have recurrent embolic events while on anticoagulation [26].
The Current Treatment Paradigm—Natural History of MR and Timing of Surgical Therapy
Medical therapy offers little for the treatment of severe MR, so the current treatment paradigm relies primarily on surgical repair or replacement of the MV. To understand the role and timing of surgical intervention in this current treatment paradigm, one must first consider the risks and benefits of surgical intervention and understand the natural history of MR, and how the interplay of these factors determines the current surgical paradigm for MR.
Surgery for Mitral Regurgitation
Surgical therapy for MR can be broadly grouped into two categories: MV repair and MV replacement. These procedures pose a risk of morbidity and mortality that increases with worsening MR and LV dysfunction [66]. As a result, at later stages of MR, the risks associated with surgery may be prohibitively high, precluding safe surgical intervention. Therefore, one of the major goals in the current treatment paradigm is to identify cases of MR and intervene surgically before the patients become too sick to tolerate surgery and have a low likelihood of surviving the operation.
At the other end of the spectrum, with regard to patients with MR and healthy ventricles, surgery is offered only to patients for whom the potential benefits of surgical correction of MR outweigh the risks. In this regard, some patients with MR can be considered “too healthy” for surgery and are monitored for progression of the disease until they fall within the appropriate therapeutic window.
Further complexity arises when the choice is made between MV replacement and repair. Mitral valve replacement involves placing a prosthetic valve in the heart, incurring a lifelong risk of infection. One must also consider the durability of the prosthetic valve. Replacement valves can be broadly categorized into mechanical valves and bioprosthetic tissue valves. Mechanical valves are extremely durable and may last for the patient’s lifetime, but they pose certain risks. These include valve thrombosis and resultant embolization, which can result in stroke or other embolic phenomena, as well as the risk of bleeding incurred by lifelong anticoagulation with warfarin to prevent such thrombosis. Mechanical valves can also fail by developing infra-annular pannus, which impairs leaflet function and reduces the effective orifice area.
Bioprosthetic valves do not necessitate systemic anticoagulation with warfarin and therefore do not pose the attendant risks. However, bioprosthetic valves have limited durability; their life span averages 10–20 years and is lower in younger patients. Significant bioprosthetic valve deterioration then results in the need for reintervention and redo valve replacement, which usually carries a higher risk of morbidity and morbidity than primary valve replacement.
In contrast, MV repair does not incur the device-related risks of anticoagulation and bioprosthetic valve deterioration, because the native valve remains in place [67, 68]. Furthermore, with contemporary valve repair, the chordal apparatus is maintained; studies show preservation of LV geometry and systolic function and also lower rates of late complications than with prosthetic MV replacement [69]. However, not all valves can be repaired, even at the best referral centers. In addition, the risks, benefits, durability, and complications of surgery must be balanced against the natural history of MR, to further elucidate the best timing for surgery and to better identify patients for whom surgical intervention is appropriate.
Natural History of MR
The natural history of MR varies substantially with severity, cause, and symptomatology. When treatment options are considered for patients with MR, it is important to distinguish between patients with symptomatic versus asymptomatic disease, and among patients with mild-to-moderate, moderate-to-severe, and severe MR.
As much as 20% of the population has trivial or mild-to-moderate MR; however, most of these individuals are asymptomatic, and for many, their MR never becomes significant enough to warrant surgical intervention [70, 71]. Furthermore, MR can remain mild or mild-to-moderate for many years without any significant worsening, either hemodynamically or in terms of symptoms. Affected patients are monitored for the development of significant hemodynamic changes or symptoms.
Although the development of symptoms is an indication for surgical intervention, it is an unpredictable and unreliable indicator of progression to moderate-to-severe or severe MR, of a chronic compensated state of MR, or of transition to a decompensated state. For example, by the time significant dyspnea arises, there may already be significant irreversible ventricular dysfunction. Thus, most patients with MR will be monitored for the development of significant anatomic, echocardiographic, or hemodynamic changes that indicate worsening MR. However; even patients with significantly worsening MR can remain asymptomatic.
The natural history of asymptomatic, moderately severe MR is controversial. Initial studies suggested a benign prognosis, without death or deterioration of LV function for up to 5 years of follow-up, but a 10% average annual risk of symptom development leading to surgical correction was noted [72]. Subsequent studies have shown a 5-year combined incidence of 42% for the onset of atrial fibrillation, heart failure, or cardiovascular death [73].
As MR progresses to the severe stage, if left untreated, its natural history involves worsening clinical deterioration, morbidity, and substantial mortality risk. This holds true in both symptomatic and asymptomatic patients. Thus, it is clear that such patients should be considered for surgery; however, as described previously, these patients are at risk for significant LV dysfunction, which can be difficult to detect and which substantially increases the likelihood of morbidity and mortality with operative intervention. Thus, patients who have developed severe LV dysfunction may be too sick for surgery and may thus fall out of the therapeutic window.
Indications for surgery for mitral regurgitation. AF atrial fibrillation, CAD coronary artery disease, CRT cardiac resynchronization therapy, ERO effective regurgitant orifice, HF heart failure, LV left ventricular, LVEF left ventricular ejection fraction, LVESD left ventricular end-systolic dimension, MR mitral regurgitation, MV mitral valve, MVR mitral valve replacement, NYHA New York Heart Association, PASP pulmonary artery systolic pressure, RF regurgitant fraction, RVol regurgitant volume, Rx therapy. ∗Mitral valve repair is preferred over MVR when possible. From Nishimura et al. [26]
Comorbidities
In addition to the risks and benefits of surgery and the natural history of MR itself, one must also consider comorbid conditions and the increased risks of morbidity, mortality, and complications they may pose. Two of the strongest risk factors for early mortality are age and NYHA functional class [66]. Continued heart failure is the main cause of death after surgical correction of MR [66]. Important predictors of late mortality after operation include advanced age, elevated serum creatinine level, elevated systolic blood pressure, coronary artery disease, advanced functional class heart failure, and echocardiographic evidence of reduced LVEF and worsening end-systolic dimension [66, 68, 74]. Renal failure or dysfunction, liver failure or dysfunction, a hostile chest due to prior sternotomy or radiation, COPD, prior stroke, endocarditis, and poor nutritional status are other factors and comorbidities that increase the risks associated with surgery and that may portend poorer outcomes. Thus, appropriate candidates for surgery are those patients who fall within the therapeutic window, and for whom the risks posed by comorbid conditions are low enough so as to not preclude surgical intervention.
Understanding this paradigm is important, as it lays the framework for understanding how emerging technologies for endovascular treatments—MV repair, MV replacement, and interventions to alleviate ventricular dysfunction—can alter the therapeutic window. This paradigm also informs what threshold levels of risk can be tolerated, and what threshold levels of benefit need to be exceeded, to ensure successful adoption of any given technique or technology.
Mitral Valve Repair
Despite the lack of randomized trials comparing MV repair and replacement in degenerative valve disease, comparative studies have demonstrated a survival advantage with MV repair [75–77]. In addition, repair preserves ventricular function and provides greater freedom from thromboembolic and anticoagulation-related events, as well as endocarditis.
The basic principles of any mitral repair include (1) reestablishing normal leaflet motion , (2) obtaining an adequate surface of leaflet coaptation , and (3) annular stabilization with a ring or band while maintaining an adequate mitral orifice size. To perform the most durable repair, the surgeon needs to be familiar with both the normal functional anatomy and the pathological anatomy as it relates to the lesions of the leaflets, leaflet motion, and annulus.
Repair techniques have evolved into three basic concepts. The first involves resectional techniques , which were popularized by Carpentier. This entails resecting abnormal leaflet tissue and later reconstruction. The second involves a “respect all, rather than resect” technique. With this approach, the free edges of the prolapsing leaflet segments are resuspended with artificial Gore-Tex neochords. Multiple variations of this approach have been described. The third concept combines the first 2: resecting all abnormal leaflet tissue, then using Gore-Tex neochords to address any remaining redundant leaflet tissue.
The edge-to-edge technique , which was popularized by Alfieri, has been used as both a primary repair strategy and a “bailout” technique. This technique provides a functional, as opposed to an anatomical, repair of the valve.
Carefully evaluating the valvular deformity by both preoperative and intraoperative echocardiography is essential. Thereafter, the surgeon must correlate these findings with the intraoperative valve analysis. Each of the leaflet segments, including commissures, chordae, and the subvalvular apparatus, as well as the annulus, must be carefully inspected. Many surgeons use P1 as a reference point to assess the degree of prolapse of the adjacent scallops because, in the majority of cases, P1 is free of disease. Others reject this concept and instead take a targeted approach to the valve by addressing the most significant lesion first and repairing additional defects thereafter. The surgeon must take into consideration the amount of leaflet tissue involved (volume) in relation to adjacent normal leaflet, the height of the affected leaflet, and the amount of support (chordae) that is lacking or in excess. Leaving the posterior leaflet too long (i.e., >1.5 cm) can lead to systolic anterior motion of the MV.
Today, more than 90% of cases of degenerative MV disease can be repaired at referral or expert centers. Furthermore, after surgeons obtain sufficient experience in minimally invasive surgery, essentially every repair technique can be applied. Minimally invasive approaches to mitral surgery provide unimpeded, direct, and truly anatomic visualization of the MV. One must keep in mind that these approaches do not help surgeons to improve their competency with mitral repair techniques. Proficiency with a wide variety of mitral repair techniques is acquired with experience and repetition. A significant learning curve is associated with both mitral repair and minimally invasive access. Considering that among surgeons performing MV surgery, the median number of MV repairs per surgeon is 5 per year, proficiency in repair may be difficult to obtain. In addition, among all surgeons performing mitral surgery, the median MV repair rate is 41% [78]. Therefore, the concept of centers of excellence has been proposed in order to obtain the highest possible rate of durable repairs [79].
Furthermore, in 2008, 26% of Society of Thoracic Surgeons Adult Cardiac Surgery Database centers were performing a median of 3 less-invasive procedures per year [80]. Therefore, the necessary skillsets to perform complex MV repairs via a minimally invasive approach may be obtainable only at minimally invasive MV repair referral centers.
Mitral Valve Repair Techniques
Posterior Leaflet Prolapse or Flail
A P2 prolapse is the most common dysfunction seen in degenerative MV disease. A small segment of flailed or prolapsed leaflet can be managed with a limited triangular resection. In contrast, a broad scallop with a large area of prolapse or flailed segment can be addressed with a quadrangular resection. This can be performed along with a sliding or folding plasty. With larger resections, annular compression sutures can be considered, as well. An alternative approach is a butterfly resection of a broad P2 segment. In certain cases in which a limited triangular resection is performed and there is excess height in P2, a Gore-Tex chord can be added to avoid potential systolic anterior motion (SAM) of the MV. With excessive leaflet tissue, a larger quadrangular resection of P2 will help avoid SAM, as well.
Prolapse of P1 and P3 can be addressed with limited resection, depending on the thickness and amount of tissue on the affected scallop. Alternatively, a complete “respect rather than resect” approach can be taken by placing polytetrafluoroethylene (PTFE) artificial neochords. Several methods can be used. These include placing individual chords in the papillary muscles supported with or without pledgets, running one Gore-Tex suture through the papillary muscle and then into the leaflet and back multiple times, placing one small Gore-Tex loop in the papillary muscle and then passing multiple individual Gore-Tex sutures through the loop and into the leaflets as necessary, and using the multi-loop technique . This approach displaces the leaflets into the ventricle and establishes a new line of coaptation to simulate a Roman arch.
Anterior Leaflet Prolapse or Flail
Mild anterior leaflet prolapse usually does not need to be addressed and resolves once the annuloplasty is placed. For moderate or greater anterior prolapse or flail, placing artificial neochords is the most commonly used technique. Various methods have been described. Single or multiple Gore-Tex neochords can be placed from the papillary muscle to the free edge of the leaflet. It is important that the neochords cross neither the midline nor each other. The length of the leaflet can be determined by measuring the height of an adjacent normal native chordae or with the saline test after annuloplasty implantation. Another method involves using premeasured Gore-Tex loops. The length of these loops can be determined by measuring adjacent normal chordae intraoperatively or by measuring normal chordae with intraoperative TEE. These chordal loops for the anterior leaflet usually measure between 22 and 26 mm. Aggressively shortening the anterior leaflet can lead to residual MR and even SAM. Another reference point that can be considered for determining the chordal length is the annular plane; the free edge of the leaflet should reach the level of the annulus. Even with these methods, measuring an exact length can be challenging.
In addition, anterior leaflet secondary chords (which are usually the appropriate length) can be transferred to the free edge. These chords can serve as a guide to the proper length of an artificial neochord if one is needed for additional support.
Other, infrequently used alternative techniques include chordal transposition , which is effective but can potentially damage a normal posterior leaflet; this technique involves transposing a segment of normal posterior leaflet with native chordae of normal length to the affected segment of prolapsing anterior leaflet. Papillary muscle repositioning involves anchoring the fibrous head of the anterior papillary muscle to the posterior papillary muscle. Resecting the anterior leaflet is reserved for significant localized abnormalities of the leaflet, and resection is limited to no more than 10% of the leaflet .
Bileaflet Prolapse
Bileaflet prolapse can be treated with a combination of the previously described techniques. These are the most challenging of all repairs, as well as the least durable. Bileaflet prolapse presenting with only a central jet identified by preoperative TEE can occasionally be addressed with only an annuloplasty ring that is sized to the annulus. Another approach to bileaflet prolapse is an Alfieri stitch (edge-to-edge repair) with the addition of an annuloplasty ring.
Commissural Prolapse
Limited commissural prolapse can be treated with a limited resection or folding plasty. With more extensive commissural prolapse secondary to leaflet destruction and chordal rupture, a quadrangular resection with annular plication can be performed. This procedure can be completed with a “magic stitch” to restore coaptation. In cases with more extensive involvement of the commissure, both A3 and P3 can be detached from the annulus after a quadrangular resection is performed. Annular plication and leaflet advancement are performed thereafter.
Patients with intact leaflets and elongated chordae can be treated with papillary muscle shortening or a papillary muscle sliding plasty. Another option is using artificial neochordae to reduce the height of the commissure.
Mitral Annular Calcification
Annular decalcification may be required to establish an adequate surface of leaflet coaptation in patients undergoing repair. The leaflet is detached from the annulus, and an attempt is made to resect the calcium bar en bloc. If this is not possible, fractional debridement with a rongeur can be performed, after which the leaflet is reattached. An ultrasonic debridement device can also facilitate the decalcification. Some cases may require patch repair of the atrioventricular groove to avoid a disruption. In cases of diffuse calcification, an alternative is to place annular sutures around the calcium and to modify the annuloplasty ring or band if necessary. Mitral annular calcification can pose a challenge, and the feasibility of repair may be limited.
Rheumatic Valvular Disease
In developing countries, attempts to repair a rheumatic valve in the earlier stages of the disease are complicated by the need for reoperation due to progressive distortion and fibrosis of the leaflets secondary to progression or recurrence of the rheumatic process. Replacement attempts are also plagued by several complications, as well as the risks associated with multiple operations, especially in young patients.
In developed countries, the disease process is different, and the leaflets undergo more of an advanced, end-stage histologic process that is unlikely to progress except for the development of calcium deposition. Annular dilatation is the cause of regurgitation in more than half of cases. Mitral repair is technically more feasible and yields better results in this group.
Repair for rheumatic mitral disease includes several techniques, ranging from commissurotomy, subvalvular chordal, and papillary muscle splitting to leaflet peeling and leaflet extension [81]. The initial step is to free the fused commissures and subvalvular apparatus by splitting the fused chords and papillary muscles. Shortened secondary chords are cut to free the leaflets even further. In some cases, even thickened restricted primary chords are transected and replaced with artificial Gore-Tex chords. The leaflets can be made more pliable by peeling off the inflammatory fibrotic layer and decalcification. When the leaflet and subvalvular mobilization are not enough to compensate for tissue retraction, performing leaflet augmentation techniques can increase the surface area of the leaflet, providing greater mobility and surface area for leaflet coaptation. Leaflet augmentation can be performed with autologous pericardium, bovine pericardium, or a collagen matrix, and on the anterior or posterior leaflet, or both leaflets. The leaflet extension technique also allows the insertion of a larger annuloplasty ring or band [81].
Annular Stabilization
Annular stabilization with a full ring or band is essential to the long-term durability of the repair. The choice between a full ring and a band is a topic of ongoing debate. The size of the annuloplasty is usually determined by the height of the anterior leaflet, although in cases of extreme myxomatous degeneration with voluminous leaflets and a very dilated annulus, a “true sized” annuloplasty is recommended. The annuloplasty restores the normal 4:3 ratio of the MV, increases the line of coaptation of the leaflets, and prevents annular dilatation. Some reports state that after a band is placed, the annulus between the trigones may continue to dilate and contribute to recurrent MR. On the other hand, others believe that a full ring can lead to mitral stenosis.
Edge-to-Edge
This technique, originally described by Alfieri [82], has been applied to degenerative disease with bileaflet prolapse, flail leaflet, and calcified annulus. The middle portion of each leaflet is identified by assessing the subvalvular apparatus with nerve hooks. Wide clefts are usually closed. The repair is completed by taking large bites through the rough zone of the leaflet tissue and suturing the free edge of A2 and P2 with a running 4 or 5-0 Prolene suture. The running length is variable but commonly covers the whole length of the mid scallop. With flail segments other than A2 or P2, the location of the suture will correspond to the center of the flailed segment. An annuloplasty is performed at the end of the procedure [83].
The minimum ring or band size should be 32 mm. Failure to use annular stabilization will increase the failure rate. Mitral annular calcification also contributes to long-term failure.
Mitral Valve Replacement
Mitral valve replacement is reserved for patients with end-stage Barlow disease, previous failed attempts to repair the MV, a heavily calcified mitral annulus, or certain forms of rheumatic disease. The replacement procedure should spare the chords to maintain annular papillary continuity. The different options include preserving the posterior leaflet and chords and resecting the entire anterior leaflet; preserving the posterior leaflet and chords, then detaching the entire anterior leaflet from the annulus and incorporating it into the posterior suture line; preserving the posterior leaflet and chords and resecting only A1 and a portion of P2, leaving P3 intact; and resecting all leaflets and chords and resuspending the papillary muscles with Gore-Tex neochords, which are passed through the annulus and onto the sewing cuff of the valve (typically placed at 4 and 8 o’clock). In patients with mitral annular calcification, if sutures can be passed through the calcium, decalcification may be avoidable. If a large segment of calcium is present and precludes suture placement, the segment will need to be resected.
Some patients have valves that are not amenable to repair, so replacement is indicated. These include patients with irreparable complex valve disease, as well as elderly patients with multiple comorbidities, for whom the benefit of repair is outweighed by the risks. A good MV replacement is better than a bad MV repair.
Surgical Treatment of Functional Mitral Regurgitation
Annular Techniques
Secondary MR, also known as functional MR, is most often caused by ischemic or dilated cardiomyopathy . The MR is caused by changes in the LV that distort the valvular apparatus. Specifically, dilation of the LV results in inferior and lateral papillary muscle displacement, which ultimately leads to tethering of the valve leaflets and loss of central coaptation.
Left ventricular end-systolic volume index (LVESVI) can be used as a surrogate for LV dilation and remodeling associated with ischemic myocardial disease and is a predictor of poor prognosis in these patients. The principles of mitral valve surgery are to restore valve competence, reduce the LVESVI, and induce reverse remodeling of the LV, which may be associated with better outcomes [84]. For patients with secondary MR, the most commonly used technique is implanting a downsized annuloplasty ring [84–91].
However, the high recurrence rate of MR associated with repair, as compared to mitral valve replacement, has prompted further examination of the two approaches to secondary MR. Recently, the Cardiothoracic Surgical Trials Network conducted a randomized controlled trial of MV repair versus replacement for patients with severe ischemic MR. Unlike many of the previous studies, this trial showed no difference in overall LV remodeling or survival for patients who underwent repair versus replacement [92]. Furthermore, the rate of recurrence of moderate or severe MR was much higher with repair than with replacement (32.6% vs. 2.3%). On the other hand, patients who underwent repair but did not have recurrent MR had significant reverse LV remodeling. In addition, the absence of MR recurrence was associated with better quality of life. This finding prompted a search for predictors of recurrent MR in order to improve patient selection for MV repair.
A subgroup analysis by Kron and colleagues [93] identified only basal aneurysm as an independent risk factor for MR recurrence. This finding suggests that leaflet tethering plays a significant role in the recurrence of MR after repair. Other possible predictors include specific echocardiographic measurements , including leaflet tethering height, tenting area, coaptation distance, LVESVI, and ventricular sphericity index [89, 94–100]. Recently, follow-up studies have suggested that 3D echocardiography may be superior to 2D echocardiography at predicting MR recurrence [101]. In addition, a 3D echocardiography study identified a P3 tethering angle of 29.9° or larger as an independent risk factor for MR recurrence [102].
Subvalvular Techniques of Mitral Valve Repair for Ischemic Mitral Regurgitation
Chordal Cutting
Encircling the base of the papillary muscles with a Gore-Tex graft
Compared with conventional MV repair, chordal-cutting MV repair has been associated with a reduced risk of recurrent MR because this repair produces greater reductions in tenting area and greater mobility of the anterior leaflet (as measured by a reduction in the distance between the free edge of the anterior MV leaflet and the posterior LV wall) without compromising postoperative LVEF [104].
Papillary Muscle Relocation
Papillary muscle relocation techniques for secondary MR are used to treat severe leaflet tethering and displacement of the coaptation point. One technique includes placing a 3-0 polypropylene suture through the posterior papillary muscle fibrous tip and then passing it through the adjacent mitral annulus just posterior to the right fibrous trigone [105]. After the mitral annuloplasty is performed, if the saline test reveals inadequate leaflet coaptation (typically in the P3 segment), the relocation suture is tightened, drawing the posterior papillary muscle tip closer to the annulus.
Another technique is the “ring plus string” repair [106, 107]. This technique is performed by anchoring a Teflon-pledgeted suture in the head of the posterior papillary muscle, then passing it through the fibrosa (midseptal annular saddle horn) under direct vision and exteriorizing it through the aortic wall underneath the commissure between the noncoronary and left coronary aortic cusps. The suture is then tied under echocardiographic guidance in the loaded, beating heart to reposition the displaced posterior papillary muscle toward the fibrosa. This technique has been refined to allow further reduction of the septal-lateral diameter after the loaded, beating heart is implanted with a DYANA nitinol-based dynamic annuloplasty device that can be deformed by activation with radiofrequency [108].
Papillary muscle relocation with a suture plus nonrestrictive mitral annuloplasty promotes a significant reversal of LV remodeling, a decrease in tenting area and coaptation depth, and less recurrent MR [109]. What remains to be seen is whether restrictive mitral valve annuloplasty produces better results than nonrestrictive annuloplasty. This raises the question of whether the annuloplasty technique or the subvalvular repair contributes more to the success of MV repair for FMR.
Papillary Muscle Approximation
Diagram showing sling around base of papillary muscles
Intraoperative photo of sling placed around the base of the papillary muscles
Photo of PTFE graft tightly approximating the base of the papillary muscles
Rigid annuloplasty ring , true sized to the anterior leaflet
The “sling and ring” repair has shown promise with regard to promoting LV remodeling and leaflet mobility by limiting the tethering secondary to displacement of the papillary muscles [110]. This anatomical correction can lead to improvements in ventricular diameter, LVEF, volume, and sphericity index.
A similar subvalvular approach to PMA consists of placing a single U-shaped stitch, reinforcing it with two patches of autologous pericardium, and passing it through the posterior and anterior papillary muscles [113]. This method of PMA lowers the rate of recurrent MR [113] and is believed to promote significant ventricular remodeling, reducing mean LVEDD and increasing mean LVEF [113]. This is consistent with the Cardiothoracic Surgery Network trial that showed that patients with more complex tethering may benefit from additional subvalvular procedures [92].
Surgical Ventricular Reconstruction
In certain populations, adding left ventriculoplasty to MV repair for FMR has been associated with more effective control of MR and further improvement of LVEF than restrictive mitral annuloplasty alone [114]. Surgical ventricular reconstruction (SVR) was first popularized for the management of heart failure with LV remodeling caused by coronary artery disease, and SVR was shown to reduce LV volume, increase LVEF, and improve ventricular function [115, 116]. In the STICH trial, despite a significantly greater reduction in LV volume with SVR than with coronary artery bypass grafting alone, this improvement did not translate into a measurable survival benefit for patients [117].
An additional study has shown that when compared with annuloplasty alone, the addition of left ventriculoplasty significantly improved LVEF in patients with an enlarged LV (LVEDD >65 mm) and severe mitral tethering. There was also a nonsignificant trend toward greater improvement in MR grade when a left ventriculoplasty was performed [118].
Endovascular Devices for the Treatment of Mitral Regurgitation
In patients with severe MR, observational studies have demonstrated that surgery to repair or replace the MV was found to improve survival more effectively than medical therapy [119]. However, surgery can pose significant risks, including a 1–5% risk of mortality and a 10–20% risk of morbidities including stroke, reoperation, renal failure, and prolonged ventilation. Elderly patients and those with LV dysfunction are at even greater risk [120]. Even in patients with moderate-to-severe MR, and in asymptomatic patients, the risks posed by surgery are not trivial, which inspired the current paradigm of monitoring patients until symptom develop, MR or LV dysfunction worsens, or sequelae of MR arise such as atrial fibrillation or pulmonary hypertension—at which point the benefits of surgery justify the risks [119, 121]. In contrast, at experienced referral centers treating patients who have a >90% chance of successful repair, the benefits of surgery justify the risks for a broader range of indications, such that guidelines recommend considering MV repair even for asymptomatic patients with normal LV function [26].
The risks posed by surgery, combined with other factors such as patient preference for less-invasive therapies, the recent successes and rapid adoption of devices for transcatheter aortic valve replacement (TAVR) , and the large, unmet clinical need for therapies for patients who are outside of the therapeutic window of surgery, have stimulated an explosion in the development of endovascular technologies for treating MR. Interest is especially great in therapies for high-risk patients deemed too sick for surgery.
Whereas TAVR for the treatment of aortic stenosis has enjoyed quick adoption and widespread success due to several factors (e.g., a singular pathophysiology of valve disease; the anatomy of the aortic annulus, which allows for precise stent-valve delivery; the ability to leverage conventional imaging techniques), the advancement of transcatheter MV interventions has been relatively slow. Endovascular therapy for MR poses far more complex challenges in terms of the anatomy, structure, and function of the MV apparatus, complex pathophysiological considerations, challenges in patient selection, imaging complexities, and comparison to gold-standard surgical approaches that include both repair and replacement. Nevertheless, a plethora of device technologies exist or are in development and the devices can be broadly categorized into repair and replacement devices.
Emerging Mitral Valve Repair Devices
Just as a variety of different surgical techniques exist to address and repair various lesions and associated dysfunction of the MV, a variety of devices are in development, largely mimicking surgical repair tech niques, with the aim of producing results comparable to those of surgical repair but by a transvascular approach. Emerging devices can be categorized by where they are placed and their mechanism of action within the MV apparatus, including annulus-based devices, leaflet-based devices, chordal-based devices, and papillary muscle-based devices.
Annulus-Based Devices
Several device technologies are in development to replicate one of the mainstay techniques of surgical MV repair, namely mitral annuloplasty . These devices can be subdivided into direct and indirect annuloplasty devices. Direct annuloplasty devices seek to mimic surgical annuloplasty techniques; a variety of these devices are placed directly into the mitral annulus. Existing direct annuloplasty devices include the Edwards Cardioband device, the ValCare Amend device, the MitraSpan Transapical Segmented Reduction Annuloplasty (TASRA) device , and the Millipede Medical IRIS device.
Direct Annuloplasty Devices
Edwards Cardioband
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